Format

Send to

Choose Destination
Mol Ther. 2019 Jul 30. pii: S1525-0016(19)30328-4. doi: 10.1016/j.ymthe.2019.07.015. [Epub ahead of print]

Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers.

Author information

1
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
2
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
3
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
4
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA.
5
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
6
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
7
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
8
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: gregory.beatty@pennmedicine.upenn.edu.

Abstract

This phase I study investigated the safety and activity of lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin (CART-meso) in patients with malignant pleural mesothelioma, ovarian carcinoma, and pancreatic ductal adenocarcinoma. Fifteen patients with chemotherapy-refractory cancer (n = 5 per indication) were treated with a single CART-meso cell infusion. CART-meso cells were engineered by lentiviral transduction with a construct composed of the anti-mesothelin single-chain variable fragment derived from the mouse monoclonal antibody SS1 fused to intracellular signaling domains of 4-1BB and CD3zeta. Patients received 1-3 × 107 or 1-3 × 108 CART-meso cells/m2 with or without 1.5 g/m2 cyclophosphamide. Lentiviral-transduced CART-meso cells were well tolerated; one dose-limiting toxicity (grade 4, sepsis) occurred at 1-3 × 107/m2 CART-meso without cyclophosphamide. The best overall response was stable disease (11/15 patients). CART-meso cells expanded in the blood and reached peak levels by days 6-14 but persisted transiently. Cyclophosphamide pre-treatment enhanced CART-meso expansion but did not improve persistence beyond 28 days. CART-meso DNA was detected in 7/10 tumor biopsies. Human anti-chimeric antibodies (HACA) were detected in the blood of 8/14 patients. CART-meso cells were well tolerated and expanded in the blood of all patients but showed limited clinical activity. Studies evaluating a fully human anti-mesothelin CAR are ongoing.

KEYWORDS:

CAR; adoptive cell therapy; chimeric antigen receptor T cell; immunotherapy; mesothelin; mesothelioma; ovarian cancer; pancreatic ductal adenocarcinoma

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center